Acenaphthene derivatives

ABSTRACT

ACENAPHTHENE DERIVATIVES ARE PROVIDED HAVING THE GENERAL STRUCTURE   5-(NH2-CO-C(-R2)(-R1)-)ACENAPHTHENE   WHEREIN AT LEAST ONE OF R1 AND R2 IS ALKYL OR SUBSTITUTED AMINOAKYL   (-A-N(-R3)-R4)   AND THE OTHER CAN BE HYDROGEN, WHEREIN R3 AND R4 ARE HYDROGEN OR A HYDROCARBON RADICAL, AND A IS ALKYLENE. THESE COMPOUNDS POSSESS ANTI-INFLAMMATORY ACTIVITY.

United States Patent Ofice 3,712,925 Patented Jan. 23, 1973 US. Cl.260-558 A 4 Claims ABSTRACT OF THE DISCLOSURE Acenaphthene derivativesare provided having the general structure wherein at least one of R andR is alkyl or substituted and the other can be hydrogen, wherein R and Rare hydrogen or a hydrocarbon radical, and A is alkylene. Thesecompounds possess anti-inflammatory activity.

The present invention relates to acenaphthene derivatives and moreparticularly to acenaphthene nitriles and amides havinganti-inflammatory activity and to intermediates for the preparation ofthese new compounds.

The compounds of this invention are useful as antiinfiarnmatory agentsand are effective in the prevention and inhibition of granuloma tissueformation in warm blooded animals, for example, in a manner similar toindomethacin. They may be used to decrease joint swelling tenderness,pain and stiffness, in mammalian species, e.g., in conditions such asrheumatoid arthritis. A compound of Formula I or a physiologicallyacceptable salt (when applicable) of the character described hereinaftermay be compounded according to accepted pharmaceutical practice in oraldosage forms such as tablets, capsules, elixirs or powders foradministration of about 100 mg. to 2 gm. per day, preferably 100 mg. to1 gm. per day in two to four divided doses. For example, about 150mg./kg./day is effective in reducing paw swelling in rats.

The acenaphthene derivatives of the invention have the general formulal-C-NH:

wherein R and R are the same or dilferent and at least one must be alkylhaving from one to about eight carbon atoms and preferably from aboutone to about three carbon atoms, or substituted aminoalkyl and the othercan be hydrogen. R and R can be the same or different and can behydrogen or a hydrocarbon radical including alkyl having from one toabout eight and preferably from one to about six carbon atoms, alkenylhaving from two to about eight and preferably from two to about fivecarbon atoms, phenyl and alkylphenyl or phenylalkyl having from seven toabout fifteen and preferably from seven to about ten carbon atoms, and Ais alkylene having from one to about six and preferably from one toabout four carbon atoms in the linking group.

The alkyl radicals included in the compounds of the invention arestraight, branched chain or cyclic radicals containing from about one toabout eight carbon atoms and preferably from about three to about eightcarbon ,atoms, and include, for example, methyl, ethyl, propyl,

isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, Z-methyl-nbutyl,neopentyl, n-hexyl, Z-methyl-n-pentyl, 3-methylpentyl,2,2-dimethyl-2-butyl, 2,3-dimethyLn-butyl, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.

Examples of suitable alkenyl radicals include ethenyl, l-butenyl,2-propenyl and B-pentenyl.

Examples of suitable alkylphenyl radicals include all isomers of tolyl,xylyl, mesityl, and butylphenyl.

The phenylalkyl radicals are preferably phenyl lower alkyl radicals,wherein the lower alkyl group contains up to about six carbon atoms,such as benzyl, phenethyl, and phenylbutyl.

Examples of suitable alkylene radicals (A) include methylene, ethylene,trimethylene, and tetramethylene as well as any of these containingalkyl side chains.

Preferred are those compounds wherein R is dimethylaminoethyl ordimethylaminopropyl and R is isopropyl.

As to the salts of the compounds of the invention, where applicable,those coming within the purview of this invention include the non-toxicphysiologically acceptable acid-addition salts. Acids useful forpreparing these acidaddition salts include, inter alia, inorganic acids,such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid),sulfuric acid, nitric acid, and phosphoric acid, and organic acids, suchas maleic, methane sulfonic, cyclohexane sultamic, tartaric, citric,acetic and succinic acids.

Examples of compounds falling within the present invention include, butare not limited to, the following:

&

/ -CNH: CtHt Q Further in accordance with the present invention aprocess is provided for preparing the compounds of claim 1, whichcomprises, dehydrating 5-acenaphtheneacetamide, for example, by reactingit with phosphorus pentoxide or thionyl chloride to formS-acenaphtheneacetonitrile having the structure HaCN then alkylating thenitrile II by reacting it in the presence of a base such as, forexample, sodium hydride or sodium amide with an alkylating agent of thestructure (III) R X wherein X is Cl, Br or I, and R is as definedhereinbefore, in a molar ratio of 112111 of within the range of fromabout 4:1 to about 1:1 at a temperature within the range of from about20 to about 40 C. to form a nitrile of the structure R-iH-CN and finallyhydrolyzing the nitrile IV by reacting it with an acid such aspolyphosphoric acid, a mineral acid such as sulfuric acid, or an organicacid such as acetic acid or mixtures of such acids or an alkali metal alkoxide such as potassium-t-butoxide to form a compound of the structureR I -CNH: H ll Nitrile IV can be further alkylated by reacting it in thepresence of a base such as sodium amide with an alkylating agent of thestructure wherein R and X are as defined above in a molar ratio of IV:IVof within the range of from about 4:1 to about 1:1 to form a nitrile ofthe structure (VII) which is hydrolyzed by reacting it withpolyphosphoric acid or any of the acids mentioned hereinbefore to form acompound of the structure (VIII) The intermediates II, IV and VII arenovel compounds and as such are a part of the present invention and canbe represented by the formula in which case R and R are as definedhereinbefore with the exception that each can be hydrogen. Examples ofsuch compounds include compound II and compounds IV and VII wherein Rand R can be any of the radicals set out hereinbefore within respect tocompounds of Formula I.

The following examples further illustrate the invention.

EXAMPLE 1 S-acenaphtheneacetonitrile A solution ofS-acenaphtheneacetamide (3.8 g.) in toluene (400 ml.) is treated withphosphorus pentoxide (12 g.) and refluxed for 90 min. The mixture isevaporated and the residue treated with Water and extracted withchloroform. The chloroform extracts are washed with saturated sodiumbicarbonate solution, 8% salt solution, dried (Na SO and evaporated. Theresidue in benzene is added to a dry-packed alumina column (75 g.) andeluted with benzene and benzene-chloroform (9:1 and 4:1). The nitrilecontaining fractions are evaporated and the residue is crystallized fromchloroform-isopropyl ether to give the title compound (2.03 g., M.P.95-95.5). Recrystallization from isopropyl ether gives the analyticalsample: M.P. 95-955 i 4.45,.; 79. 3% 6.60 s, 1,-2-oH,oH,); 5.97 (S,-CH2CN) Analysis.-Calcd. for C H N (percent): C, 87.01; H, 5.74; N,7.25. Found (percent): C, 86.93; H, 5.87; N, 7.09.

EXAMPLE 2 a-Isopropy1-5-acenaphtheneacetonitrile A solution of 500 mg.of S-acenaphtheneacetonitrile in ml. of dimethylformarnide is cooled inan ice bath and treated with 111 mg. of sodium hydride and stirred for0.5 hr. The mixture is treated with 0.44 ml. of isopropyl iodide andstirred at room temperature overnight. The mixture is poured into waterand extracted with ether. The ether extracts are washed with water, 8%salt solution, dried (Na SO and evaporated. Plate chromatography of theresidue on silica gel using chloroformhexane (1:1) as the developingsolvent gives a major band which is eluted with ethyl acetate andevaporated to give the title compound (382 mg. as an oil). Theanalytical sample is prepared by distillation at 100' (0.02 mm.):

x 4.46 3,13% 6.60 s, 1,2 oH,-oH,- 5.68

(d., J=5.5 cps., 5-CHCN) Analysis.Calcd. for C17H17N (percent): C,87.48; H, 7.28; N, 5.95. Found (percent): C, 87.14; H, 7.32; N, 5.53.

EXAMPLE 3 a-[2- (dimethylamino)ethylJl-S-acenaphtheneacetonitrile,hydrochloride A solution of 4.13 g. of 5-acenaphtheneacetonitrile in ml.of dimethylformamide is cooled in an ice bath and treated with 1.0 g. ofsodium hydride and stirred for 45 min. The mixture is treated with 2.3g. of dimethylaminoethylbromide and stirred at room temperatureovernight. The mixture is diluted with water and extracted with ether.The ether extracts are washed with 8% salt solution and then extractedwith 2 N HCl. The acidic fraction is made alkaline and extracted withether. The ether extracts are washed with 8% salt solution, dried (Na SOand evaporated. The residue is distilled to give 3.5 g. of an oil whichis dissolved in ether and converted to a hydrochloride salt with I-IClin methanol. The product is crystallized from ethanol-ether to give thetitle compound (3.72 g., M.P. 171-173"). The analytical sample isprepared by recrystallization from ethanol-ether: M.P. 171- 173;

AXE 4.48 2

Analysis.-Calcd. for C H N Cl (percent): C, 71.89; H, 7.08; N, 9.32; Cl,11.79. Found (percent): C, 71.63; H, 7.34; N, 9.15; Cl, 11.78;

EXAMPLE 4 a- [Z-(dimethylamino) ethyl]-a-isopropyl-5-acenaphtheneacetonitrile A solution of 3.31 g. ofa[=2-(dimethylamino)ethyl]- 5-acenaphtheneacetonitrile in 50 .ml. ofether is treated with 0.48 g. of sodium amide and stirred and refluxedfor 7 hours. The suspension is cooled and treated with 3.5 ml. ofisopropyl bromide and stirred and refluxed for three days. The mixtureis treated with water and ether and the ether layer is separated. Theaqueous layer is extracted with additional ether. The combined etherfractions are washed with 8% salt solution, dried (Na SO and evaporated.The residue is crystallized from isopropyl ether-hexane to give thetitle compound (2.05 g., M.P. 89-90). Recrystallization from isopropylether gives the analytical sample: M.P. 90-91";

A '4A8 195% 7.90 (S, Me N), 6.60 s, morn-on.

Analysis.-Calcd. for C H N (percent): C, 82.31; H, 8.55; N, 9.14. Found(percent): C, 82.04; H, 8.71; N, 9.16.

EXAMPLE 5 a-[2-(dimethylamino)ethyl]-5-acenaphtheneacetamide Asuspension of 250 mg. of a-[Z-(dimethyIamino)ethyl]-5-acenaphtheneacetonitrile, hydrochloride in 5 ml. ofpolyphosphoric acid is. stirred at ,for 1.5 hrs. The mixture is pouredinto ice water and stirred until solution is achieved. The aqueousfraction is extracted with ether and then made alkaline. The alkalinefraction is extracted with chloroform and the chloroform extracts washed(1:1) and evaporated to give 121 mg. of the title comwith 8% saltsolution, dried (Na SO and evaporated. pound. The analytical sample isprepared by distillation The residue is crystallized fromacetone-isopropyl ether and solidifies on standing: M.P. 77-79;

to give the title compound (196 mg., M.P. 183-184).

Recrystallization from acetone gives the analytical sam- 5 6 01 1; 5% zand 6.60 Analysis.-Calcd. for C H N O (percent): C, 77.73; (S, 1,2-CH-CH H, 8.70; N, 8.63. Found (percent): 'C, 77.65; H, 8.59;

Analysis.Calcd. for C H N 0 (percent): C, 76.56; H, 7.85; N, 9.92. Found(percent): C, 76.29; H, 8.06; EXAMPLES 7 TO 14 N, 9.76.

EXAMPLE 5 Following the procedure of Examples 1, 3 and 5 butsubstituting for the dimeth laminoethl bromide the0"[2'(d1methy1amm)ethyn'aflsopmpyl's' compound shown in the left handcol mn of Table I acenaphtheneacetamlde below the product shown in theright hand column is A solution of 500 mg. ofa-[2-(dimethylamino)ethyl]- obtained.ot-isopropyl-S-acenaphtheneacetonitrile in 1.5 m1. of acetic TABLE I IIR- CNH2 Ex. No.- R X R1 7 CzHs 0% M- :)4- CH3 CH1 for hrs. The mixtureis poured into water, made alkaline with potassium carbonate andextracted with 70 Following the procedure of Examples 1, 3, 4 and 6chloroform. The chloroform extracts are washed with but substituting forthe dimethylaminoethyl bromide in 8% salt solution, dried (Na SO andevaporated. Plate Example 3 the R X compound shown in Column 1 ofchromatography of the residue on silica gel using ethyl Table II andsubstituting for the isopropyl bromide the acetate-methanol (7:3) as thedeveloping solvent gives R X compound shown in Column 2, the productshown a major band whiGh is eluted with ethyl acetate-methanol in Column3 is obtained.

2. A compound according to claim 1 having the for- References Cited mulaUNITED STATES PATENTS 3,282,964 11/1966 Szarvasi et a1. 260-558 53,257,420 6/1966 Szarvasi et a1. 260-558 0 3,573,304 3/1971 Eberle eta1. 260-558 O OTHER REFERENCES B Ianczewsl-u et 211., ChemicalAbstracts, vol. 62, col. wherein R is 10 49697 (1965) R3 Smith,Open-Chain Nitrogen Compounds, v01. 1, p. 143 (1965). --AN 4 HENRY R.JILES, Primary Examiner I 3. A compound of claim 1 having the name oc[2-H. I. MOATZ, Assistant Examiner (dimethylamino)ethyl]-u-isopropy1 5acenaphtheneacetamide. US. Cl. X.R.

4. A compound of claim 1 having the name oz[Z-(di- 26O 465 R 465 E 5methy1amino)propy1]-a-isopropyl 5 acenaphtheneacet- 20 amide.

